A Study Evaluating the Efficacy and Safety of Mitapivat (AG-348) in Participants With Sickle Cell Disease (RISE UP)

Phase 2

Active, not recruiting

• Conditions: Sickle Cell Disease
• Interventions: Drug: Mitapivat; Other: Mitapivat-matching placebo

• Registration Number: NCT05031780
• Lead Sponsor: Agios Pharmaceuticals, Inc.

Brief Summary

This clinical trial is a Phase 2/3 study that will determine the recommended dose of mitapivat and evaluate the efficacy and safety of mitapivat in sickle cell disease by testing how well mitapivat works compared to placebo to increase the amount of hemoglobin in the blood and to reduce or prevent the occurrence of sickle cell pain crises. In addition, the long-term effect of mitapivat on efficacy and safety will be explored in an open-label extension portion.

Detailed Description

Mitapivat is a small molecule, oral activator of pyruvate kinase R (PKR). PKR is involved with maintaining health, energy, and longevity of red blood cells (RBCs). The study aims to evaluate the efficacy and safety of treatment with mitapivat in participants with sickle cell disease. The study is a Phase 2/3 study in which the recommended dose of mitapivat will be selected and further evaluated. The Phase 2 portion includes a 12-week randomized, placebo-controlled period in which participants will be randomized in a 1:1:1 ratio to receive 2 dose levels of mitapivat or placebo. The Phase 3 portion includes a 52-week randomized, placebo-controlled period in which participants will be randomized in a 2:1 ratio to receive the recommended mitapivat dose level or placebo. Participants who complete either the Phase 2 or Phase 3 portion will have the option to move into a 216-week open label extension period to receive mitapivat.

Study Timeline

• Study First Submitted: 2021-07-29
• Study First Submitted QC: 2021-08-30
• Study First Posted: 2021-09-02
• Study Start: 2022-02-11
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-18
• Last Update Posted: 2025-07-20
• Primary Completion: 2025-10
• Study Completion: 2030-02-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 286

Inclusion Criteria

• Age 16 years or older (18 years or older [France and Germany]); participants age 16 or 17 years must physically have completed puberty;
• Documented diagnosis of sickle cell disease (SCD) (HbSS, HbSC [combined heterozygosity for hemoglobins S and C], HbS/beta 0- thalassemia, HbS/ beta plus thalassemia, or other sickle cell syndrome variants);
• At least 2 SCPCs and no more than 10 SCPCs in the past 12 months;
• Hemoglobin at least 5.5 and 10.5 gram per deciliter (g/dL) at the most. Hemoglobin concentration must be based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period;
• If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 days before starting study drug. Discontinuation of hydroxyurea requires a 90-day washout prior to informed assent/consent;
• Women capable of becoming pregnant must agree to use 2 forms of contraception.

Exclusion Criteria

• Pregnant, breastfeeding, or parturient;
• Receiving regularly scheduled transfusions;
• Hepatobiliary disorders including but not limited to significant liver disease or gallbladder disease;
• Severe kidney disease;
• Prior exposure to gene therapy or prior bone marrow or stem cell transplantation;
• Currently receiving treatment with a disease-modifying therapy for SCD (eg, voxelotor, crizanlizumab, L-glutamine), with the exception of hydroxyurea. The last dose of voxelotor, crizanlizumab, and L-glutamine must have been administered at least 90 days before randomization;
• Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered at least 90 days before starting study drug;
• Received treatment on another investigational trial within 90 days prior to start of study drug or plans to participate in another investigational drug trial;
• Taking medications that are strong inhibitors of CYP3A4/5 or strong inducers of CYP3A4 that cannot be stopped in an acceptable timeframe before starting study drug (timeframe will be discussed with your doctor).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 2: Mitapivat 50 mg BID	Mitapivat	Double-blind Period: Mitapivat 50 milligrams (mg) twice daily (BID) for 12 weeks.
Phase 2: Mitapivat 100 mg BID	Mitapivat	Double-blind Period: Mitapivat 100 mg BID for 12 weeks.
Phase 2: Placebo	Mitapivat-matching placebo	Double-blind Period: Mitapivat-matching placebo for 12 weeks.
Phase 2: Open-Label Extension Period	Mitapivat	Participants who received mitapivat 50mg BID in the double-blind period may choose to receive mitapivat 50mg BID for 216 weeks after. Participants who received mitapivat 100mg BID in the double-blind period may choose to receive mitapivat 100 mg BID for 216 weeks after. Participants who received mitapivat-matching placebo in the double-blind period, may be randomized to receive either mitapivat 50 mg or 100 mg BID for 216 weeks after.
Phase 3: Placebo	Mitapivat-matching placebo	Double-blind Period: Mitapivat-matching placebo for 52 weeks.
Phase 3: Mitapivat 100 mg BID	Mitapivat	Double-blind Period: Mitapivat 100 mg BID for 52 weeks.
Phase 3: Open-Label Extension Period	Mitapivat	Participants may choose to receive mitapivat 100 mg BID for 216 weeks after the Double-blind Period. Participants who received mitapivat-matching placebo in the double-blind period, may choose to receive mitapivat 100 mg BID for 216 weeks after the Double-blind Period.

Primary Outcome Measures

Name	Time	Method
Phase 3: Percentage of Participants With Hb Response	Week 52
Phase 3: Annualized Rate of Sickle Cell Pain Crises (SCPCs)	Up to Week 52
Phase 2: Percentage of Participants With Hemoglobin (Hb) Response	Week 12
Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs)	Up to Week 12

Secondary Outcome Measures

Name	Time	Method
Phase 2: Mitapivat Area Under the Concentration	Day 1 up to Week 8
Phase 3: Mitapivat Area Under the Concentration Curve	Day 1 up to Week 40
Phase 3: Change From Baseline in 6-Minute Walk Test (6MWT)	Baseline, Week 52
Phase 2: Change From Baseline in Indirect Bilirubin	Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Lactate Dehydrogenase (LDH)	Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Erythropoietin	Baseline, Week 10 up to Week 12
Phase 2: Mitapivat Concentration Over Time	Day 1 up to Week 8
Phase 3: Change From Baseline in Absolute Reticulocytes	Baseline, Week 24 up to Week 52
Phase 3: Percentage of Participants With Improvement in the Patient Global Impression of Change (PGIC) -Fatigue	Baseline, Weeks 24, 28, 40, and 52
Phase 3: Annualized Rate of Emergency Room Visits for SCPC	Up to Week 52
Phase 2: Change From Baseline in Hb Concentration	Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Patient-Reported Outcomes Measurement Information System® (PROMIS®) Fatigue 13a Short Form (SF) Score	Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Absolute Reticulocytes Count	Baseline, Week 10 up to Week 12
Phase 2: Change From Baseline in Percent Reticulocytes	Baseline, Week 10 up to Week 12
Phase 2: Annualized Rate of SCPCs	Up to Week 12
Phase 3: Change From Baseline in Indirect Bilirubin	Baseline, Week 24 up to Week 52
Phase 3: Change From Baseline in Percent Reticulocytes	Baseline, Week 24 up to Week 52
Phase 3: Change From Baseline in PROMIS® Fatigue 13a SF Scores	Baseline, Week 24 up to Week 52
Phase 3: Time to Second SCPC	Up to Week 52
Phase 2: Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in Adenosine Triphosphate (ATP) and 2,3-Diphosphoglycerate (2,3-DPG)	Day 1 up to Week 8
Phase 3: Change From Baseline in LDH Concentration	Baseline, Week 24 up to Week 52
Phase 3: Time to First SCPC	Up to Week 52
Phase 3: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs)	Up to 56 weeks
Phase 3: Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in ATP and 2,3-DPG Levels	Day 1 up to Week 40
Phase 3: Mitapivat Concentration Over Time	Day 1 up to Week 40
Phase 2: Mitapivat Maximum (Peak) Concentration	Day 1 up to Week 8
Phase 3: Change From Baseline in Erythropoietin	Baseline, Week 24 up to Week 52
Phase 3: Change From Baseline in Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Pain Impact	Baseline, Week 24 and 52
Phase 3: Change From Baseline in Hb Concentration	Baseline, Week 24 up to Week 52
Phase 3: Annualized Frequency of Hospitalizations for SCPC	Up to Week 52
Phase 3: Percentage of Participants With Improvement in the Patient Global Impression of Severity (PGIS) -Fatigue	Baseline, Weeks 24, 28, 40, and 52
Phase 3: Annualized Rate of Hospitalization Days for SCPC	Up to Week 52
Phase 3: PGIC of Pain	Baseline, Week 52
Phase 3: Change From Baseline in PGIS of Pain	Baseline, Week 52
Phase 3: Change From Baseline in PROMIS Pain Intensity	Baseline, Week 24 and 52
Phase 3: Mitapivat Maximum (Peak) Concentration	Day 1 up to Week 40

Trial Locations

Locations (89)

University of California San Diego; 🇺🇸 La Jolla, California, United States

UCLA Health; 🇺🇸 Los Angeles, California, United States

Children's Hospital Oakland; 🇺🇸 Oakland, California, United States

University of Connecticut Health Center; 🇺🇸 Farmington, Connecticut, United States

Children's National Hospital; 🇺🇸 Washington, District of Columbia, United States

MedStar Washington Hospital Center; 🇺🇸 Washington, District of Columbia, United States

Sylvester Comprehensive Cancer Center-Miami; 🇺🇸 Miami, Florida, United States

University of Chicago Medical Center; 🇺🇸 Chicago, Illinois, United States

Riley Hospital For Children; 🇺🇸 Indianapolis, Indiana, United States

LSU Health Sciences Center - Shreveport; 🇺🇸 Shreveport, Louisiana, United States

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